A one-hit model of cell death in inherited neuronal degenerations (vol 406, pg 195, 2000)

In genetic disorders associated with premature neuronal death, symptoms may not appear for years or decades. This delay in clinical onset is often ass umed to reflect the occurrence of age-dependent cumulative damage(1-6). For example, it has been suggested that oxidative stress disrupts metabolism i n neurological degenerative disorders by the cumulative damage of essential macromolecules(1,4,7). A prediction of the cumulative damage hypothesis is that the probability of cell death will increase over time. Here we show i n contrast that the kinetics of neuronal death in 12 models of photorecepto r degeneration, hippocampal neurons undergoing excitotoxic cell death(8), a mouse model of cerebellar degeneration(9) and Parkinson's(10) and Huntingt on's diseases are all exponential and better explained by mathematical mode ls in which the risk of cell death remains constant or decreases exponentia lly with age. These kinetics argue against the cumulative damage hypothesis ; instead, the time of death of any neuron is random. Our findings are most simply accommodated by a 'one-hit' biochemical model in which mutation imp oses a mutant steady state on the neuron and a single event randomly initia tes cell death. This model appears to be common to many forms of neurodegen eration and has implications for therapeutic strategies.